A Study of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) Plus Daratumumab in People With Monoclonal Gammopathy of Renal Significance (MGRS)

Inclusion Criteria:

Inclusion criteria for cast nephropathy associated with MM:

* Subjects must have a confirmed diagnosis of NDMM as per standard IMWG criteria
* Subjects must have measurable disease, defined as meeting at least 1 of the following criteria ≤ 14 days prior to registration:

  * A monoclonal Immunoglobulin (M-protein) concentration on serum protein electrophoresis (SPEP) of ≥ 0.5 g/dL.
  * Measurable urinary light chain secretion by quantitative analysis using urine protein electrophoresis (UPEP) of ≥ 200 mg/24 hours.
  * Involved serum free light chain (FLC) level ≥ 10 mg/dL, provided the serum FLC ratio is abnormal.
* eGFR must be \<40 ml/min/1.73m2
* Subjects must have histologically confirmed diagnosis of monoclonal gammopathy associated CN by kidney biopsy OR If a kidney biopsy is not available, a percentage of urine albumin excretion (%UAE) \< 25 % AND FLC \> 50 mg/dL

Inclusion criteria for other MGRS associated renal diseases

* Histologically confirmed diagnosis of MGRS-associated renal disease by kidney biopsy
* Presence of monoclonal gammopathy by serum protein electrophoresis, Immunofixation, or Free Light Chain Assay
* Evidence of plasma cell dyscrasia by bone marrow biopsy confirming clonal plasma cell population
* eGFR \<40 ml/min/1.73m2 or 24h urine total protein \> 1gm

Inclusion criteria for both cast nephropathy associated with MM and other MGRS associated renal diseases

* Subjects must be ≥ 18 years of age at time of registration.
* Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ≤ 14 days prior to registration.
* No evidence of unequivocal recent nephrotoxic exposure (NSAIDs, radiocontrast…)
* No evidence of obstructive nephropathy by ultrasound
* Subjects must have adequate hematology laboratory values within 14 days prior to registration defined by the following:

  * Neutrophils ≥ 1.0 × 10\^9 /L (Patients cannot have received G-CSF or GM-CSF within 1 week of screening or pegfilgrastim within 2 weeks of screening to meet eligibility).
  * Platelets ≥ 100 × 10\^9 /L for run-in and 75 × 10\^9 /L for phase II (Note: Platelet support is not permitted to help participants meet eligibility criteria).
  * hemoglobin ≥ 7.5 g/dL without prior red blood cells \[RBC\] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted.
* Subjects must have adequate hepatic function laboratory values ≤ 14 days prior to registration:

  * Aspartate aminotransferase (AST), alkaline phosphatase (AP) or alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN)
  * Total bilirubin ≤ 1.5 x ULN except for patients with a history of elevated total bilirubin, such as in Gilbert's.
  * Hepatic Child-Pugh score at worse A (patients are eligible for the phase 2 part but not for the Run-in-Period of the trial).
* Female patients will have to satisfy the following criteria:

  * Be postmenopausal for at least 1 year Prior to registration visit, OR
  * Be surgically sterile, OR
  * If of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR
  * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception). If patient is female and of childbearing potential, she must have a negative serum beta human chorionic gonadotropin (β-HCG) test \< 14 days prior to registration and consent to ongoing pregnancy testing during the course of the study.
* Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following

  * Practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
  * Practice true abstinence when this is in line with the preferred and usual lifestyle of he subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception).
* Subjects must have the willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, study procedures, and research procedures.

Exclusion Criteria:

* MGRS associated with diseases other than plasma cell dyscrasia (e.g. CLL, B-cell neoplasm, Waldenstrom's macroglobulinemia…)
* Plasma cell leukemia, AL amyloidosis, or POEMS syndrome.
* Treatment with prior drugs aimed at the plasma cell dyscrasia.
* Treatment with prior or concurrent investigational agents aimed at the plasma cell dyscrasia.
* Female patients who are lactating or have a positive serum pregnancy test during the screening period.
* Major surgery ≤ 14 days before registration.
* Focal radiation therapy within 14 days prior to registration with the exception of palliative- radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.
* Disease-related central nervous system involvement.
* The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection.
* Clinically significant cardiac disease, including:

  * Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
  * Uncontrolled cardiac arrhythmia
* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
* Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
* Concurrent malignancy except for treated non-melanoma skin cancer, cervical carcinoma in situ and low-risk prostate CA being monitored without treatment.
* Grade 2 or higher peripheral neuropathy on clinical examination during the screening period.
* Chemotherapy ≤ 14 days of registration.
* Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic halflives, whichever is longer.
* Patients with known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \<50% of predicted normal; moderate or severe persistent asthma within the past 2 years. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is \<50% of predicted normal
* Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
* Patients who have a contraindication to the use of any form of anticoagulation or antiplatelet agents.
* The use of strong CYP3A4 and CYP1A2 inducers or inhibitors will not be allowed while patients are treated on this study.
* Patients with Hepatic Child-Pugh score B and C. Note that patients with Hepatic Child-Pugh score A are excluded from the Run-in-Period of the trial
* Patient is:

  * Known history of human immunodeficiency virus (HIV) and those who are seropositive for HIV.
  * Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen \[anti-HBc\] and/or antibodies to hepatitis B surface antigen \[anti-HBs\]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
  * Seropositive for hepatitis C (except in the setting of a sustained virologic response \[SVR\], defined as aviremia at least 12 weeks after completion of antiviral therapy).
  * Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
  * Plasmapheresis within 28 days before randomization.